US7101877B2 - Ion channel modulating compounds and uses thereof - Google Patents

Ion channel modulating compounds and uses thereof Download PDF

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Publication number
US7101877B2
US7101877B2 US10/674,684 US67468403A US7101877B2 US 7101877 B2 US7101877 B2 US 7101877B2 US 67468403 A US67468403 A US 67468403A US 7101877 B2 US7101877 B2 US 7101877B2
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Prior art keywords
cyclohexane
trans
morpholinyl
hydrogen
compound
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US10/674,684
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English (en)
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US20050020481A1 (en
US20050192208A2 (en
Inventor
Allen I Bain
Gregory N Beatch
Cindy J Longley
Bertrand M C Plouvier
Tao Sheng
Michael J. A. Walker
Richard A. Wall
Sandro L Yong
Jeff Jiqun Zhu
Alexander B Zolotoy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Correvio Canada Corp
Advanz Pharma Switzerland SARL
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Cardiome Pharma Corp
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Priority to US10/674,684 priority Critical patent/US7101877B2/en
Assigned to CARDIOME PHARMA CORP. reassignment CARDIOME PHARMA CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAIN, ALLEN I., LONGLEY, CINDY J., WALKER, MICHAEL J.A., ZOLOTOY, ALEXANDER B., BEATCH, GREGORY N., ZHU, JEFF J., SHENG, TAO, YONG, SANDRO L., WALL, RICHARD A., PLOUVIER, BERTRAND
Priority to US10/914,841 priority patent/US7507545B2/en
Priority to US11/018,428 priority patent/US7057053B2/en
Publication of US20050020481A1 publication Critical patent/US20050020481A1/en
Publication of US20050192208A2 publication Critical patent/US20050192208A2/en
Priority to US11/342,270 priority patent/US7259184B2/en
Priority to US11/450,921 priority patent/US20070004718A1/en
Application granted granted Critical
Publication of US7101877B2 publication Critical patent/US7101877B2/en
Priority to US11/619,136 priority patent/US20070190156A1/en
Priority to US11/757,880 priority patent/US7524879B2/en
Priority to US11/944,282 priority patent/US7534790B2/en
Priority to US12/408,587 priority patent/US20090270478A1/en
Priority to US12/412,010 priority patent/US8008342B2/en
Priority to US12/424,450 priority patent/US7875611B2/en
Priority to US12/970,532 priority patent/US20110207730A1/en
Priority to US13/110,574 priority patent/US20120095073A1/en
Priority to US13/678,299 priority patent/US20130171077A1/en
Priority to US14/081,792 priority patent/US20140314685A1/en
Assigned to MIDCAP FUNDING V, LLC reassignment MIDCAP FUNDING V, LLC SECURITY INTEREST Assignors: ARTESIAN THERAPEUTICS, INC., CARDIOME INTERNATIONAL AG, CARDIOME PHARMA CORP., CARDIOME UK LIMITED, CARDIOME, INC., CORREVIO (AUSTRALIA) PTY LTD., CORREVIO (UK) LTD., CORREVIO INTERNATIONAL SARL, CORREVIO LLC, MURK ACQUISITION SUB, INC.
Priority to US14/632,713 priority patent/US20160008322A1/en
Assigned to CARDIOME, INC., CORREVIO LLC, CORREVIO INTERNATIONAL SARL, MURK ACQUISITION SUB, INC., CARDIOME UK LIMITED, ARTESIAN THERAPEUTICS, INC., CORREVIO (UK) LTD., CARDIOME PHARMA CORP., CORREVIO (AUSTRALIA) PTY LTD., CARDIOME INTERNATIONAL AG reassignment CARDIOME, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FINANCIAL TRUST
Assigned to CORREVIO CANADA CORP. reassignment CORREVIO CANADA CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARDIOME PHARMA CORP.
Assigned to CORREVIO INTERNATIONAL SÀRL reassignment CORREVIO INTERNATIONAL SÀRL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CORREVIO CANADA CORP.
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    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention is generally directed toward ion channel modulating compounds, pharmaceutical compositions and kits containing the ion channel modulating compounds, and therapeutic uses thereof.
  • Cardiac ion channels are proteins that reside in the cell membrane and control the electrical activity of cardiac tissue. In response to external stimuli, such as changes in potential across the cell membrane, ion channels can form a pore through the cell membrane, and allow movement of specific ions into or out of the cell.
  • the integrated behavior of thousands of ion channels in a single cell results in an ion current, and the integrated behavior of many ion currents makes up the characteristic cardiac action potential.
  • Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these will be first heart attacks and 450,000 will be recurrent attacks. About one-third of the people experiencing these attacks will die of them. At least 250,000 people a year die of coronary heart disease with 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.
  • myocardial infarction or fatal coronary heart disease defined as myocardial infarction or fatal coronary heart disease.
  • Atrial fibrillation is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E. L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031–2; Kannel and Wolf, Am. Heart J. 123(1):264–7 January 1992). Its prevalence is likely to increase as the population ages and it is estimated that 3–5% of patients over the age of 60 years have AF (Kannel W. B., Abbot R. D., Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018–22, 1982; Wolf P. A., Abbot R.
  • Class Ia, Ic and III antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48(3):345–71, 1994).
  • drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G. K., Circulation. 83(6):2248–50, 1990; Coplen S. E., Antman E. M., Berlin J. A., Hewitt P., Chalmers T. C., Circulation 1991; 83(2):714 and Circulation 82(4):1106–16, 1990; Flaker G.
  • Class III antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M., Drugs. 48(3):345–71, 1994; Capucci A., Aschieri D., Villani G. Q., Drugs & Aging 13(1):51–70, 1998).
  • Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30–50% for recent onset AF (Capucci A., Aschieri D., Villani G.
  • cardiac pathological conditions may be treated and/or prevented by the use of one or more ion channel modulating compounds that either singly or together with one or more additional compounds are able to selectively inhibit certain combination of cardiac ionic currents. More specifically, the cardiac currents referred to above are the sodium currents and early repolarising currents.
  • Early repolarising currents correspond to those cardiac ionic currents which activate rapidly after depolarization of membrane voltage and which effect repolarisation of the cell.
  • Many of these currents are potassium currents and may include, but are not limited to, the transient outward current I to1 such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (I Kur ) such as Kv1.5, Kv1.4 and Kv2.1).
  • the ultrarapid delayed rectifier current (I Kur ) has also been described as I sus .
  • a second calcium dependent transient outward current (I to2 ) has also been described.
  • the cardiac pathological conditions that may be treated and/or prevented by the present invention may include, but are not limited to, arrhythmias such as the various types of atrial and ventricular arrhythmias.
  • the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents.
  • the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents under conditions where an “arrhythmogenic substrate” is present in the heart.
  • An “arrhythmogenic substrate” is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation and those conditions that precede the onset of arrhythmias such as atrial fibrillation.
  • the present invention provides aminocyclohexyl ether compounds of formula (I), or a solvate or pharmaceutically acceptable salt thereof:
  • X is selected from a direct bond, —C(R 6 ,R 14 )—Y— and —C(R 13 ) ⁇ CH—, with the proviso that when X is a direct bond and A is formula (III) then at least one of R 7 , R 8 and R 9 is not hydrogen;
  • Y is selected from a direct bond, O, S and C 1 –C 4 alkylene
  • R 13 is selected from hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl and benzyl;
  • R 1 and R 2 are independently selected from hydrogen, C 1 –C 8 alkyl, C 3 –C 8 alkoxyalkyl, C 1 –C 8 hydroxyalkyl, and C 7 –C 12 aralkyl; or
  • the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 –C 3 hydroxyalkyl, oxo, C 2 –C 4 acyl, C 1 –C 3 alkyl, C 2 –C 4 alkylcarboxy, C 1 –C 3 alkoxy, C 1 –C 20 alkanoyloxy, or may be substituted to form a Spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 –C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted
  • R 1 and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]-hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl;
  • R 3 and R 4 are independently attached to the cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 –C 6 alkyl and C 1 –C 6 alkoxy, and, when both R 3 and R 4 are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur;
  • A is selected from C 5 –C 12 alkyl, a C 3 –C 13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl and C 1 –C 6 alkyl;
  • R 10 and R 11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl;
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and R 17 is selected from hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl
  • the present invention provides a composition or medicament that includes a compound according to formula (I) in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains a compound according to formula (I).
  • the present invention provides pharmaceutical compositions that contain at least one compound of formula (I) in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further provides for methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or preventing a disease or condition from arising in a warm-blooded animal, wherein a therapeutically effective amount of a compound of formula (I), or a composition containing a compound of formula (I) is administered to a warm-blooded animal in need thereof.
  • arrhythmia diseases of the central nervous system, convulsion, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular diseases, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other metal disorder, and alopecia.
  • the present invention provides a pharmaceutical composition containing an amount of a compound of formula (I) effective to produce local analgesia or anesthesia in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention further provides a method for producing, local analgesia or anesthesia in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I).
  • These compositions and methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal.
  • the present invention provides a pharmaceutical composition containing an amount of a compound of formula (I) effective to enhance the libido in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention further provides a method for enhancing libido in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I).
  • These compositions and methods may be used, for example, to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire of a patient without a sexual dysfunction.
  • the therapeutically effective amount may be administered to a bull (or other breeding stock), to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program.
  • the present invention provides a compound of formula (I) or composition containing a compound of formula (I), for use in methods for either modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro.
  • FIG. 1 illustrates the reaction sequence further described in Example 1, for preparing an aminocyclohexyl ether compound of the present invention.
  • FIG. 2 illustrates a procedure whereby either cis- or trans-aminocyclohexyl ether compounds of the present invention may be prepared.
  • FIG. 3 illustrates synthetic methodology that may be employed to prepare either cis or trans stereoisomers of the compounds of the present invention.
  • FIGS. 4A and 4B illustrate the synthetic methodology described in Example 15.
  • the present invention provides for the treatment and/or prevention of a variety of cardiac pathological conditions by the use of one or more ion channel modulating compounds that either singly, or together with one or more additional compounds, are able to inhibit selective cardiac ionic currents. More specifically, the cardiac currents referred to above are the sodium currents and early repolarising currents.
  • Early repolarising currents correspond to those cardiac ionic currents which activate rapidly after depolarisation of membrane voltage and which effect repolarisation of the cell.
  • Many of these currents are potassium currents and may include, but are not limited to, the transient outward current (I to1 such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (I Kur such as Kv1.5, Kv1.4, and Kv2.1).
  • the ultrarapid delayed rectifier current (I Kur ) has also be described as I sus .
  • a second calcium dependent transient outward current (I to2 ) has also been described.
  • the cardiac pathological conditions that may be treated and/or prevented by the novel methods of the present invention may include, but are not limited to, arrhythmias such as the various types of atrial (supraventricular) and ventricular arrhythmias.
  • arrhythmias such as the various types of atrial (supraventricular) and ventricular arrhythmias.
  • the compounds of the present invention are especially useful in treating and/or preventing atrial fibrillation and ventricular fibrillation.
  • an “arrhythmogenic substrate” is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation (Janse & Wit, Physiol. Rev. 69(4):1049–169, October 1989), and those conditions that precede the onset of arrhythmias such as atrial fibrillation (Pichlmaier et al. Heart 80(5):467–72, November 1998). Under conditions described above for cardiac arrhythmias in general, there is an increase in acidity of the cardiac milieu from the normal physiological pH (i.e., the pH of the milieu is lower than normal).
  • one or more ion channel modulating compounds are used to inhibit selective cardiac sodium currents and cardiac early repolarising currents. It is preferable that the ion channel modulating compounds generally have a pKa value of about 4 to 9 and more preferably less than about 8. The most preferred pKa values are between about 5 and 7.5. Methods to determine pKa values are well known in the art (see, e.g., Perrin, “Dissociation Constants of Organic Bases in Aqueous Solution”, Butterworth, London, 1972).
  • the fraction of the charged (protonated) species will be increased under the pathological conditions such as cardiac arrhythmias and the presence of an arrhythmogenic substrate in the heart as described above due to the increase in cardiac milieu acidity.
  • the charged form of a compound is active, its potency increases under conditions associated with an increases in cardiac milieu acidity.
  • one or more ion channel modulating compounds are used to inhibit selective cardiac ionic currents. More specifically, the cardiac currents referred to above are the sodium currents and early repolarising currents. It is preferable that the ion channel modulating compounds block the said cardiac currents from extracellular loci. Such compounds act on an external locus of the ion channel that is accessible from the extracellular surface. This facilitates access to the ion channel and provides rapid onset kinetics and exhibits frequency dependent blockade of currents. Such properties are all beneficial for compounds used to treat arrhythmias.
  • the novel methods of the present invention provide treatment and/or prevention of arrhythmias that do not prolong action potential duration in normal cardiac ventricle but rather prolongs action potential duration under conditions when an arrhythmogenic substrate is present in the heart.
  • Blockade of early, rather than late repolarising currents will prolong action potential duration under conditions where action potential duration has been previously reduced.
  • Blockade of early, rather than late, repolarising currents offers another advantage over existing methods.
  • Blockade of late repolarising currents such as I Kr (HERG) and I Ks (minK-LQT) prolongs action potential under normal conditions. In so doing there is a risk of precipitating a polymorphic ventricular tachycardia commonly called torsade de pointes which can be fatal (Nattel, 1998).
  • the novel methods of the present invention greatly reduce such proarrhythmia risk.
  • one or more ion channel modulating compounds are used to inhibit selective cardiac sodium currents and cardiac early repolarising currents.
  • concentration of each compound is typically between 0.001 and 30 ⁇ M.
  • the present invention is directed to ion channel modulating compounds that block cardiac early repolarising currents and cardiac sodium currents.
  • the ion channel modulating compounds block the cardiac ion channels responsible for early repolarising currents and sodium currents; and/or block cardiac early repolarising currents and cardiac sodium currents under conditions where an arrhythmogenic substrate is present in the heart; and/or block the cardiac ion channels responsible for early repolarising currents and sodium currents under conditions where an arrhythmogenic substrate is present in the heart; and/or block cardiac early repolarising currents and cardiac sodium currents from extracellular loci in cardiac cells; and/or have pKa values of between 4–9, preferably having have pKa values of between 5–7.5.
  • the cardiac early repolarising currents referred to above comprise ionic currents which activate rapidly after depolarisation of membrane voltage and which effect repolarisation of the cell.
  • the early repolarising currents may comprise the cardiac transient outward potassium current (I to ) and/or the ultrarapid delay rectifier current (I Kur ).
  • the cardiac transient outward potassium current (I to ) and/or the ultrarapid delay rectifier current (I Kur ) may comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents.
  • the invention also provides a composition comprising one or more of the above-described ion channel modulating compounds in combination with a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides that the above-described ion channel modulating compound(s) and/or composition(s) containing same may be used in a method for treating or preventing arrhythmia in a warm-blooded animal; and/or may be used in a method for modulating ion channel activity in a warm-blooded animal; and/or may be used in a method for modulating ion channel activity in vitro.
  • the invention also provides for the use of an ion channel modulating compound in a manufacture of a medicament.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) an amount of an ion modulating compound as described above effective to treat or prevent atrial arrhythmia in a warm-blooded animal in need of the treatment or prevention, and (b) a pharmaceutically acceptable carrier, diluent, or excipient.
  • this composition may be used in a method for treating or preventing atrial arrhythmia in a warm-blooded animal, where the method comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of one of the above-described ion channel modulating compounds or a composition containing same.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) an amount of an ion channel modulating compound as described above effective to treat or prevent ventricular arrhythmia in a warm-blooded animal in need of the treatment or prevention, and (b) a pharmaceutically acceptable carrier, diluent, or excipient.
  • This composition may be used in a method for treating or preventing ventricular arrhythmia in a warm-blooded animal, where the method comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of one of the above-described ion channel modulating compounds or a composition containing same.
  • the invention further provides a method for inhibiting multiple cardiac ionic current, where the method comprises administering to a warm-blooded animal in need thereof one or more compounds that either singly or together both block cardiac early repolarising currents and cardiac sodium currents, said one or more compounds being administered in an amount effective to block cardiac sodium currents and cardiac early repolarising currents.
  • said one or more compounds may either singly or together both block cardiac early repolarising currents and cardiac sodium currents from extracellular loci in cardiac cells.
  • the present invention also provides a method for inhibiting multiple cardiac ionic currents, where the method comprises administering to a warm-blooded animal in need thereof one or more compounds that either singly or together both block the cardiac ion channels responsible for early repolarising currents and sodium channels, said one or more compounds being administered in an amount effective to block the cardiac sodium ion channels and the cardiac early repolarising ion channels.
  • said one or more compounds may either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • one compound may block both sodium currents and cardiac early repolarising currents from extracellular loci in cardiac cells.
  • each of said one or more compounds may have a pKa value of less than 8.
  • the invention in addition provides a method for treating or preventing a cardiac condition wherein there is an “arrhythmogenic substrate” present in the heart, where the method comprises administering to a warm-blooded animal in need thereof, in an amount effective to treat or prevent said cardiac condition, one or more compounds that either singly or together block cardiac early repolarising currents and cardiac sodium currents.
  • said one or more compounds may either singly or together both block cardiac early repolarising currents and cardiac sodium currents from extracellular loci in cardiac cells.
  • one compound may both block cardiac early repolarising currents and cardiac sodium currents from extracellular loci in cardiac cells.
  • each of said one or more compounds may have a pKa value of less than 8.
  • the present invention provides a method for treating or preventing a cardiac condition wherein there is an “arrhythmogenic substrate” present in the heart, where this method comprises administering to a warm-blooded animal in need thereof, in an amount effective to treat or prevent said cardiac condition, one or more compounds that either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents.
  • said one or more compounds may either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • one compound may both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • each of said one or more compounds may have a pKa value of less than 8.
  • the present invention provides a method for treating or preventing a cardiac condition wherein there is an increase in acidity from the normal physiological pH of the cardiac milieu, where the method comprises administering to a warm-blooded animal in need thereof, in an amount effective to treat or prevent said cardiac condition, one or more compounds that either singly or together both block cardiac early repolarising currents and cardiac sodium currents.
  • said one or more compounds may either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • one compound may block cardiac ion channels responsible for early repolarising currents and in addition block sodium currents from extracellular loci in cardiac cells.
  • each of said one or more compounds may have a pKa value of less than 8.
  • the present invention also provides a method for treating or preventing a cardiac condition wherein there is an increase in acidity from the normal physiological pH of the cardiac milieu, where the method comprises administering to a warm-blooded animal in need thereof, in an amount effective to treat or prevent said cardiac condition, one or more compounds that either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents.
  • said one or more compounds may either singly or together both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • one compound may both block cardiac ion channels responsible for early repolarising currents and sodium currents from extracellular loci in cardiac cells.
  • each of said one or more compounds may have a pKa value of less than 8.
  • the cardiac condition is ventricular arrhythmia. In another preferred embodiment, in the above-described methods, the cardiac condition is atrial arrhythmia.
  • the increase in acidity of the cardiac milieu is due to myocardial ischaemia. Additionally, or alternatively, the increase in acidity of the cardiac milieu is due to high heart rate. Additionally, or alternatively, the increase in acidity is due to inflammation. Additionally, or alternatively, the increase in acidity is due to the presence of an “arrhythmogenic substrate” in the heart. Additionally, or alternatively, the increase in acidity is due to conditions which precede atrial fibrillation.
  • the present invention is directed to aminocyclohexyl ether compounds, pharmaceutical compositions containing the aminocyclohexyl ether compounds, and various uses for the compound and compositions.
  • uses include blockage of ion channels in vitro or in vivo, the treatment of arrhythmias, the production of anesthesia, and other uses as described herein.
  • An understanding of the present invention may be aided by reference to the following definitions and explanation of conventions used herein.
  • aminocyclohexyl ether compounds of the invention have an ether oxygen atom at position 1 of a cyclohexane ring, and an amine nitrogen atom at position 2 of the cyclohexane ring, with other positions numbered in corresponding order as shown below in structure (A):
  • bonds from the cyclohexane ring to the 1-oxygen and 2-nitrogen atoms in the above formula may be relatively disposed in either a cis or trans relationship.
  • the stereochemistry of the amine and ether substituents of the cyclohexane ring is either (R,R)trans or (S,S)-trans.
  • the stereochemistry is either (R,S)cis or (S,R)-cis.
  • a bond to a substituent and/or a bond that links a molecular fragment to the remainder of a compound may be shown as intersecting one or more bonds in a ring structure. This indicates that the bond may be attached to any one of the atoms that constitutes the ring structure, so long as a hydrogen atom could otherwise be present at that atom. Where no particular substituent(s) is identified for a particular position in a structure, then hydrogen(s) is present at that position.
  • group (B) is intended to encompass groups wherein any ring atom that could otherwise be substituted with hydrogen, may instead be substituted with either R 7 , R 8 or R 9 , with the proviso that each of R 7 , R 8 and R 9 appears once and only once on the ring. Ring atoms that are not substituted with any of R 7 , R 8 or R 9 are substituted with hydrogen.
  • the R groups may be present at different atoms of the ring, or on the same atom of the ring, so long as that atom could otherwise be substituted with a hydrogen atom.
  • the invention is intended to encompass compounds wherein —X—CH(R 5 )— is joined through X to the aryl group (VI) at any atom which forms the aryl group (VI) so long as that atom of group (VI) could otherwise be substituted with a hydrogen atom.
  • —X—CH(R 5 )— is joined through X to the aryl group (VI) at any atom which forms the aryl group (VI) so long as that atom of group (VI) could otherwise be substituted with a hydrogen atom.
  • the R 12 group would occupy one and only one of the remaining six positions, and hydrogen atoms would be present in each of the five remaining positions.
  • Z represents a divalent atom, e.g., oxygen or sulfur, then Z cannot be directly bonded to —X
  • an asymmetric divalent radical When the invention specifies the location of an asymmetric divalent radical, then that divalent radical may be positioned in any possible manner that provides a stable chemical structure. For example, for compounds containing the A—X—CH(R 5 )— group where X is C(R 14 ,R 6 )—Y—, the invention provides compounds having both the A—C(R 14 ,R 6 )—Y—CH(R 5 )— and A—Y—C(R 14 ,R 6 )—CH(R 5 )— groups.
  • a wavy bond from a substituent to the central cyclohexane ring indicates that that group may be located on either side of the plane of the central ring.
  • the compounds of the present invention contain at least two asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the aminocyclohexyl ether compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
  • independently at each occurrence is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables (e.g., R 1 within the set R 1 and R 2 ) is selected without regard the identity of the other member of the set.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid
  • “Acyl” refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl —(C ⁇ O)— group containing the specified number of carbon atoms. Examples include acetyl [CH 3 C ⁇ O—, a C 2 acyl] and propionyl [CH 3 CH 2 C ⁇ O—, a C 3 acyl].
  • Alkanoyloxy refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule. Examples include propanoyloxy [(CH 3 CH 2 C ⁇ O—O—, a C 3 alkanoyloxy] and ethanoyloxy [CH 3 C ⁇ O—O—, a C 2 alkanoyloxy].
  • Alkoxy refers to an O-atom substituted by an alkyl group, for example, methoxy [—OCH 3 , a C 1 alkoxy].
  • Alkoxyalkyl refers to a alkylene group substituted with an alkoxy group.
  • methoxyethyl [CH 3 OCH 2 CH 2 —] and ethoxymethyl [(CH 3 CH 2 OCH 2 —] are both C 3 alkoxyalkyl groups.
  • Alkoxycarbonyl refers to an ester substituent wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH 3 CH 2 OC ⁇ O—, a C 3 alkoxycarbonyl] and methoxycarbonyl [CH 3 OC ⁇ O—, a C 2 alkoxycarbonyl].
  • Alkyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include n-propyl (a C 3 alkyl), iso-propyl (also a C 3 alkyl), and t-butyl (a C 4 alkyl).
  • Alkylene refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment.
  • An example is propylene [—CH 2 CH 2 CH 2 —, a C 3 alkylene].
  • Alkylcarboxy refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [—COOH]. Examples include carboxymethyl [HOOC—CH 2 —, a C 2 alkylcarboxy] and carboxyethyl [HOOC—CH 2 CH 2 —, a C 3 alkylcarboxy].
  • Aryl refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
  • Alkyl refers to an alkylene group wherein one of the points of attachment is to an aryl group.
  • An example of an aralkyl group is the benzyl group [C 6 H 5 CH 2 —, a C 7 aralkyl group].
  • Cycloalkyl refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms.
  • An example of a cycloalkyl group is the cyclopentenyl group (C 5 H 7 —), which is a five carbon (C 5 ) unsaturated cycloalkyl group.
  • Carbocyclic refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
  • Carbocyclic aryl refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted.
  • Heteroatom refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
  • Heteroaryl refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in “Handbook of Chemistry and Physics,” 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
  • Hydroalkyl refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (—OH) group. Examples include hydroxymethyl (—CH 2 OH, a C 1 hydroxyalkyl) and 1-hydroxyethyl (—CHOHCH 3 , a C 2 hydroxyalkyl).
  • Thioalkyl refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH 3 S—, a C 1 thioalkyl).
  • Modulating in connection with the activity of an ion channel means that the activity of the ion channel may be either increased or decreased in response to administration of a compound or composition or method of the present invention.
  • the ion channel may be activated, so as to transport more ions, or may be blocked, so that fewer or no ions are transported by the channel.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences , Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • sterile saline and phosphate-buffered saline at physiological pH may be used.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Id. at 1449.
  • antioxidants and suspending agents may be used. Id.
  • “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
  • the compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
  • the “therapeutically effective amount” of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • compositions described herein as “containing a compound of formula (I)” encompass compositions that contain more than one compound of formula (I).
  • the compounds of the present invention are amines which may be represented by formula (I):
  • Compounds of formula (I) are aminocyclohexyl ethers. More specifically, these aminocyclohexyl ethers are substituted at position 2 of the cyclohexyl ring with an amine group —NR 1 R 2 .
  • the cyclohexyl ring may also be substituted with additional substituents (designated as R 3 and R 4 ) as described in more detail below. Examples of specific embodiments of compounds represented by formula (I) are described below
  • the compounds of formula (I) may be primary, secondary, or tertiary amines (i.e., both R 1 and R 2 are hydrogen, only one of R 1 and R 2 is hydrogen, or neither of R 1 and R 2 are hydrogen, respectively).
  • the compounds of formula (I) are secondary or tertiary amines, i.e., both of R 1 are not R 2 hydrogen.
  • the compounds of formula (I) are tertiary amines, i.e., neither R 1 nor R 2 is hydrogen. Where the amine is tertiary, it may be a cyclic amine.
  • Amine substituents R 1 and R 2 may be independently selected from substituents which include hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., C 1 –C 8 alkyl), alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C 3 –C 8 alkoxyalkyl), alkyl groups containing from one to eight carbon atoms where one of the carbon atoms is substituted with a hydroxyl group (i.e., C 1 –C 8 hydroxyalkyl), and aralkyl groups containing from seven to twelve carbon atoms (i.e., C 7 –C 12 aralkyl).
  • substituents which include hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., C 1 –C 8 alkyl), alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C 3 –C 8 alkoxyalkyl), alkyl groups containing
  • R 1 and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a ring denoted by formula (II):
  • the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 –C 3 hydroxyalkyl, oxo, C 2 –C 4 acyl, C 1 –C 3 alkyl, C 2 –C 4 alkylcarboxy, C 1 –C 3 alkoxy, C 1 –C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur (e.g., an acetal, thioacetal, ketal, or thioketal group); and any two adjacent additional carbon ring atoms may be fused to a C 3
  • any two adjacent ring atoms may be joined together by single or double bonds.
  • the ring of formula (II) may be saturated or unsaturated, and an unsaturated ring may contain one, or more than one, sites of unsaturation.
  • the ring of formula (II) may contain one or more double bonds, it being understood, however, that the unsaturated ring of formula (II) is chemically stable.
  • R 1 and R 2 when taken together with the 2-amino nitrogen of formula (I), may complete a bicyclic ring.
  • Bicyclic rings include, for example, 3-azabicyclo[3.2.2]nonane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.2.0]heptane.
  • the 2-substituents of the cyclohexyl ethers of formula (I) are the following groups: 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, and 3-azabicyclo[3.2.0]-heptan-3-yl.
  • R 1 and R 2 when taken together, contain only a single heteroatom.
  • Preferred heteroatoms include nitrogen, oxygen and sulfur.
  • An example of a ring in which R 1 and R 2 together include an oxygen heteroatom is the morpholinyl group.
  • An example of a ring where R 1 and R 2 together include a second nitrogen heteroatom is the piperazinyl group.
  • Cyclohexane substituents R 3 and R 4 may be independently attached to ring positions 3, 4, 5 or 6 (i.e., both R 3 and R 4 may be attached to the same ring position or each attached to different ring positions).
  • R 3 and R 4 are independently selected from hydrogen, hydroxy, C 1 –C 6 alkyl, and C 1 –C 6 alkoxy, and, when both R 3 and R 4 are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur.
  • Preferred heterocyclic substituents contain either a single oxygen or a single sulfur ring atom.
  • a compound of formula (I) may have X as a —C(R 6 ,R 14 )—Y— group, where Y may be any of a direct bond, an oxygen atom (O), a sulfur atom (S) or a C 1 –C 4 alkylene group.
  • R 6 and R 14 are independently selected from hydrogen, C 1 –C 6 alkyl, aryl and benzyl, or R 6 and R 14 , when taken together with the carbon to which they are attached, may form a spiro C 3 –C 5 cycloalkyl.
  • compounds of the invention include compounds of formula (I) where R 6 and R 14 are hydrogen and Y is a direct bond, such that X may be CH 2 .
  • X may be an alkenylene moiety, e.g., a cis-or trans-alkenylene moiety, C(R 13 ) ⁇ CH, where R 13 may be any of hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl or benzyl.
  • R 13 may be any of hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl or benzyl.
  • X is preferably a trans-alkenylene moiety.
  • X may be a direct bond.
  • R 5 is selected from hydrogen, C 1 –C 6 alkyl, aryl and benzyl.
  • X is either a —C(R 6 ,R 14 )—Y—or a C(R 13 ) ⁇ CH group, and is not a direct bond.
  • the compounds of the invention exclude those compounds wherein X is a direct bond when R 1 and R 2 are hydrogen.
  • X is selected from a direct bond, —C(R 6 ,R 14 )—Y—, and —C(R 13 ) ⁇ CH—, with the proviso that when X is a direct bond and A is formula (III) then at least one of R 7 , R 8 and R 9 is not hydrogen.
  • the compounds of the invention exclude those compounds wherein X is a direct bond when A is formula (III) and each of R 7 , R 8 and R 9 is hydrogen. In another embodiment, the compounds of the invention exclude those compounds wherein X is a direct bond when A is formula (III).
  • Ether side chain component A is generally a hydrophobic moiety.
  • a hydrophobic moiety is comprised of nonpolar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups containing nitrogen, oxygen, or sulfur ring atoms.
  • Suitable hydrocarbons are C 6 –C 12 alkyl and C 3 –C 13 carbocyclic rings.
  • Particularly preferred cyclic hydrocarbons include selected aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, acenaphthyl, and fluorenyl and are represented by formulae (III), (IV), (V), (VI), (VII), or (VIII) respectively.
  • a suitable “A” group within the compounds of the present invention is a phenyl ring represented by formula (III):
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, aryl and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl.
  • R 7 , R 8 and R 9 is preferably selected from amine (—NR 15 R 16 , where R 15 and R 16 are independently hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkylcarbonyl, C 1 –C 6 thioalkyl or aryl groups.
  • R 7 , R 8 and R 9 are preferably a substituent other than hydrogen.
  • the present invention provides compounds of formula (I) where A includes phenyl groups of formula (IIII) such that at least one of R 7 , R 8 and R 9 is not hydrogen, i.e., formula (III) is a phenyl group that contains at least one non-hydrogen substituent.
  • R 7 , R 8 and R 9 are selected from amine (—NR 15 R 16 , where R 15 and R 16 are independently hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkylcarbonyl and C 1 –C 6 thioalkyl, i.e., none of R 7 , R 8 or R 9 is aryl.
  • A does not include a phenyl ring of formula (III) when X is a direct bond.
  • R 10 and R 11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl.
  • R 10 and R 11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl, as defined above.
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and R 17 is selected from hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl
  • the aryl groups of formula (VI) are derivatives of indene, indole, benzofuran, and thianaphthene when Z is methylene, nitrogen, oxygen, and sulfur, respectively.
  • Preferred heterocyclic groups of formula (VI) include indole where Z is NH, benzofuran where Z is O, and thianaphthene where Z is S. As described below, in a preferred embodiment, Z is O, S or N—R 17 , and in a particularly preferred embodiment Z is O or S.
  • Still another suitable “A” group in compounds of the present invention is the fluorenyl group represented by formula (VIII):
  • ether side chain component A is an acenapthyl or fluorenyl group only when X is a direct bond or CH 2 .
  • the acenaphthyl group is a 1-acenaphthyl group
  • the fluorenyl group is a 9-fluorenyl group.
  • X is (CH 2 )—Y.
  • Y is preferably a direct bond, an oxygen atom, or a sulfur atom.
  • Y is a direct bond or an oxygen atom.
  • Y is a direct bond and X is C(R 6 ,R 14 ), where R 6 and R 14 are as defined above.
  • R 13 is a hydrogen atom.
  • R 3 and R 4 are preferably independently attached to the cyclohexane ring at the 4- or 5-positions.
  • the invention provides compounds having formula (IX), or a solvate or pharmaceutically acceptable salt thereof:
  • X is selected from a direct bond, —CH ⁇ CH— and —C(R 6 ,R 14 )—Y—;
  • Y is selected from a direct bond, O and S;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , A and Z are defined as above for compounds of formula (I).
  • the invention provides a compound having formula (X), or a solvate or pharmaceutically acceptable salt thereof:
  • X is selected from a direct bond, —CH ⁇ CH— and —C(R 6 ,R 14 )—Y—;
  • Y is selected from a direct bond, O, and S;
  • R 1 , R 2 , R 6 and R 14 are defined as above for compounds of formula (I);
  • R 3 and R 4 are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and C 1 –C 6 alkoxy;
  • A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V), and (VI) as above for compounds of formula (I), wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as above for compounds of formula (I).
  • the invention provides compounds having formula (XI), or a solvate or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are defined as above for compounds of formula (I);
  • R 3 and R 4 are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and methoxy;
  • A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V), and (VI) as above for compounds of formula (I), wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as above for compounds of formula (I).
  • the invention provides compounds of formula (XII), or a solvate or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are defined as above for compounds of formula (I);
  • R 3 and R 4 are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and methoxy;
  • A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V), and (VI) as above for compounds of formula (I), wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as above for compounds of formula (I).
  • the invention provides compounds of formula (XIII), or a solvate or pharmaceutically acceptable salt thereof:
  • X is selected from —C(R 6 ,R 14 )—Y— and —CH ⁇ CH—;
  • R 3 and R 4 are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and methoxy;
  • A is selected from C 3 –C 8 cycloalkyl and any of formulae (III), (IV), (V), (VI), (VII) and (VIII) as above for compounds of formula (I), where R 8 and R 9 are defined as above for compounds of formula (I); R 7 , R 10 , R 11 , and R 12 are hydrogen, and Z is selected from O, S and N—R 17 where R 17 is selected from hydrogen and methyl.
  • the invention provides compounds having formula (XIV), or a solvate or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are defined as above for compounds of formula (I);
  • A is selected from any of formulae (III), (IV), (V) and (VI) as above for compounds of formula (I), wherein R 7 , R 10 , R 11 , and R 12 , are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 , with the proviso that at least one of R 8 and R 9 is not hydrogen; and Z is selected from O and S.
  • the invention provides compounds having formula (XV), or a solvate or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are defined as above for compounds of formula (I);
  • A is selected from any of formulae (III), (IV), (V) and (VI) as defined above for compounds of formula (I), wherein R 7 , R 10 , R 11 , and R 12 , are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 , with the proviso that at least one of R 8 and R 9 is not hydrogen; and Z is selected from O and S.
  • the invention provides compounds having formula (XVI), or a solvate or pharmaceutically acceptable salt thereof:
  • X is selected from a direct bond, trans-CH ⁇ CH—, —CH 2 — and —CH 2 —O—;
  • R 1 and R 2 are both methoxyethyl or, when taken together with the nitrogen atom to which they are attached, complete a ring selected from pyrrolidinyl, 2-ketopyrrolidinyl, 3-ketopyrrolidinyl, 2-acetoxypyrrolidinyl, 3-acetoxypyrrolidinyl, 2-hydroxypyrrolidinyl, 3-hydroxypyrrolidinyl, thiazolidinyl, piperidinyl, 2-ketopiperidinyl, 3-ketopiperidinyl, 4-ketopiperidinyl, acetylpiperazinyl, 1,4-dioxa-7-azaspiro[4.4]non-7-yl, hexahydroazepinyl, morpholinyl, N-methylpiperazinyl and 3-azabicyclo[3.2.2]nonanyl; and
  • A is selected from cyclohexyl, monochlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 1-naphthyl, 2-naphthyl, 3-benzo(b)thiophenyl, 4-benzo(b)thiophenyl, (2-trifluoromethyl)phenyl, 2,4-di(trifluoromethyl)phenyl, and (4-trifluoromethyl)phenyl.
  • the invention provides compounds having formula (XVII), or a solvate or pharmaceutically acceptable salt thereof:
  • n is selected from 1, 2 and 3;
  • R 18 is either hydrogen or methyl and is independently attached to the cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-positions;
  • R 19 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen.
  • R 20 is selected from a group consisting of bromine, chlorine and fluorine;
  • the invention provides compounds having a trans configuration of formula (XVII) as represented by formula (XVIII), or a solvate or pharmaceutically acceptable salt thereof:
  • n is selected from 1, 2 and 3;
  • R 18 is either hydrogen or methyl and is independently attached to the cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-positions;
  • R 19 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen.
  • R 20 is selected from a group consisting of bromine, chlorine and fluorine;
  • the invention provides compounds having formula (IXX); or a solvate or pharmâceutically acceptable salt thereof:
  • n is selected from 1, 2 and 3;
  • R 18 is either hydrogen or methyl and is independently attached to the cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-positions;
  • R 19 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen.
  • R 20 is selected from a group consisting of bromine, chlorine and fluorine;
  • aminocyclohexyl ether compounds of the present invention contain amino and ether sidechains disposed in a 1,2 arrangement on a cyclohexane ring. Accordingly, the amino and ether sidechains may be disposed in either a cis or trans relationship, relative to one another and the plane of the cyclohexane ring.
  • the present invention provides synthetic methodology whereby cis or trans compounds may be prepared.
  • Trans compounds of the present invention may be prepared in analogy with known synthetic methodology (see, e.g., Shanklin, Jr. et al., U.S. Pat. No. 5,130,309).
  • FIG. 1 outlines the preparation of a trans compound of the invention, where this preparation is more fully described in Example 1.
  • the preparation of a trans compound of the invention may be achieved by following a four step procedure.
  • cyclohexene epoxide undergoes a ring-opening reaction with an amine. See, e.g., Szmuszkovicz, U.S. Pat. No. 4,145,435. While the reaction can occur at room temperature, typically elevated temperature is preferred in order to drive the reaction to completion in a commercially desirable length of time.
  • the reaction is typically conducted in a solvent, such as water, and the reflux temperature of the solvent provides a suitable temperature. Equal molar amounts of the amine and cyclohexene epoxide typically provide satisfactory results.
  • the amine nitrogen reacts with the epoxide group to form a 1-hydroxy 2-amino cyclohexane, where the hydroxy and amine groups are typically disposed in a trans relationship.
  • a wide variety of amine compounds and substituted cyclohexene oxides may be employed in this general reaction, and FIG. 1 illustrates this reaction in the instance where the amine is morpholine and the cyclohexene oxide is unsubstituted.
  • appropriate protection groups are introduced prior to step i) being carried out. Suitable protecting groups are set forth in, for example, Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).
  • a second step (denoted “ii)” in FIG. 1 ) the hydroxy group that was derived from the epoxide, is converted into an activated form.
  • An “activated form” as used herein means that the hydroxy group is converted into a good leaving group.
  • the leaving group illustrated in FIG. 1 is a mesylate group, and that is a preferred leaving group. However, the hydroxy group could be converted into other leaving groups according to procedures well known in the art.
  • the aminocyclohexanol compound is treated with methanesulfonyl chloride in the presence of a base, such as triethylamine as shown in FIG. 1 . The reaction is satisfactorily conducted at about 0° C.
  • an alcohol is reacted with a strong base to provide an alkoxide salt.
  • Conversion of an alcohol to an alkoxide (also known as an alcoholate) using strong base is a general reaction, and will work with a wide variety of hydroxy-containing compounds.
  • the alcohol compound may have other reactive functional groups that are desirably protected prior to contact of the alcohol with strong base. Suitable protecting groups are set forth in, for example, Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).
  • Such alcohols are either commercially available or may be obtained by procedures described in the art or adapted therefrom, where suitable procedures may be identified through the Chemical Abstracts and Indices therefor, as developed and published by the American Chemical Society.
  • a fourth step (denoted “iv)” in FIG. 1 ), the alcoholate of step “iii)” is reacted with the activated aminocyclohexanol of step “ii)”.
  • compounds of the present invention may be prepared by reacting an activated form of the appropriate 1,2-aminocyclohexanol (I mol) with an alcoholate (1.25 mol) prepared by treatment of the selected alcohol (1.25 mol) with, for example, sodium hydride (1.3 mol).
  • the 1,2-aminocyclohexanol (1 mol) can be activated by forming the corresponding mesylate, in the presence of methanesulfonyl chloride (1.25 mol) and triethylamine (1.5 mol).
  • the mesylate is added quickly to the alcoholate, in a suitable solvent such as dimethylformamide.
  • the reaction temperature is monitored carefully in order to avoid undesired side-reactions such as ⁇ -elimination. In general, a reaction temperature of 80–90° C. for 2 hours is typically suitable to form compounds of the invention.
  • the desired product is recovered from the reaction mixture by conventional organic chemistry techniques, and is purified generally by column chromatography followed by recrystallisation. Protective groups may be removed at the appropriate stage of the reaction sequence. Suitable methods are set forth in, for example, Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).
  • the reaction sequence described above (and shown in FIG. 1 ) generates the aminocyclohexyl ether as the free base.
  • the pure enantiomeric forms can be obtained by preparative chiral HPLC.
  • the free base may be converted, if desired, to the monohydrochloride salt by known methodologies, and subsequently, if desired, to other acid addition salts by reaction with inorganic or organic salts.
  • Acid addition salts can also be prepared metathetically by reacting one acid addition salt with an acid which is stronger than that of the anion of the initial salt.
  • Cis or trans compounds of the invention may be prepared according to the chemistry outlined in FIG. 2 .
  • 1,2-aminocyclohexanones may be prepared by Swern oxidation of the corresponding trans-1,2-aminocyclohexanol compounds (which may be prepared as described above) using oxalyl chloride/dimethyl sulfoxide (see, e.g., Synthesis 1980, 165). Subsequent reduction of the aminocyclohexanone with lithium aluminum hydride or sodium borohydride provides a mixture of cis- and trans-aminocyclohexanols.
  • the mixture of aminoalcohols may be esterified with an appropriate carboxylic acid by azeotropic distillation in toluene in the presence of a catalytic amount of p-toluenesulfonic acid, to provide a diastereomeric mixture of cis- and trans-esters.
  • the mixture of diastereomeric esters can be separated by preparative chromatography by one of ordinary skill in the art.
  • the racemic cis- or trans ester preparation could then be reduced with sodium borohydride in the presence of Lewis acid to the corresponding racemic cis- or trans-ether (see, e.g., J. Org. Chem. 25, 875, 1960 and Tetrahedron 18, 953, 1962).
  • the racemic cis-ether can be resolved by preparative chiral HPLC as discussed above for the trans-compound.
  • cis and trans compounds of the invention may be prepared according to the chemistry outlined in FIG. 3 .
  • cyclohexene oxide can react with an alcohol (ROH) in the present of Mg(ClO 4 ) 2 (see, e.g., M. Chini et al., Synlett, 673–676, 1992) to provide 1,2-hydroxycyclohexyl ethers.
  • ROH alcohol
  • Oxidation with pyridinium dichromate see, e.g., R. Oshima et al., J. Org. Chem., 50, 2613–2621, 1985 yielded the corresponding 1,2-alkoxycyclohexanone.
  • the present invention provides compositions which include a cyclohexylamine compound as described above in admixture or otherwise in association with one or more inert carriers, excipients and diluents, as well as optional ingredients if desired.
  • These compositions are useful as, for example, assay standards, convenient means of making bulk shipments, or pharmaceutical compositions.
  • An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001 wt % to about 75 wt % of the entire weight of the composition.
  • Inert carriers include any material which does not degrade or otherwise covalently react with a compound of the invention.
  • suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents such as acetonitrile, ethyl acetate, hexane and the like (which are suitable for use in in vitro diagnostics or assays, but typically are not suitable for administration to a warm-blooded animal); and pharmaceutically acceptable carriers, such as physiological saline.
  • HPLC High Performance Liquid Chromatography
  • the present invention provides a pharmaceutical or veterinary composition (hereinafter, simply referred to as a pharmaceutical composition) containing a cyclohexylamine compound as described above, in admixture with a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition containing an effective amount of a cyclohexylamine compound as described above, in association with a pharmaceutically acceptable carrier.
  • compositions of the present invention may be in any form which allows for the composition to be administered to a patient.
  • the composition may be in the form of a solid, liquid or gas (aerosol).
  • routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, epidural, intrasternal injection or infusion techniques.
  • Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet, capsule or cachet may be a single dosage unit, and a container of cyclohexylamine compound in aerosol form may hold a plurality of dosage units.
  • compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • inventive compositions may include one or more compounds (active ingredients) known for a particularly desirable effect.
  • active ingredients for instance, epinephrine may be combined with an aminocyclohexyl ether compound of the invention, to provide a composition useful to induce local anesthesia.
  • the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.
  • the pharmaceutical composition includes a cyclohexylamine compound as described herein, in admixture with one or more carriers.
  • the carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
  • the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
  • composition When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweeten
  • composition when in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • the composition may be in the form of a liquid, e.g., an elixir, syrup, solution, aqueous or oily emulsion or suspension, or even dry powders which may be reconstituted with water and/or other liquid media prior to use.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred compositions contain, in addition to the present compounds, one or more of a sweetening agent, thickening agent, preservative (e.g., alkyl p-hydoxybenzoate), dye/colorant and flavor enhancer (flavorant).
  • a surfactant e.g., alkyl p-hydroxybenzoate
  • wetting agent e.g., water, or other sugar syrups
  • dispersing agent e.g., sorbitol, glucose, or other sugar syrups
  • suspending agent e.g., sorbitol, glucose, or other sugar syrups
  • buffer e.g., buffer, stabilizer and isotonic agent
  • the emulsifying agent may be selected from lecithin or sorbitol monooleate.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant
  • a liquid compositions intended for either parenteral or oral administration should contain an amount of the inventive compound such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition.
  • Preferred oral compositions contain between about 4% and about 50% of the active cyclohexylamine compound.
  • Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of active compound.
  • the pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration.
  • the composition may include a transdermal patch or iontophoresis device.
  • Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 25% w/v (weight per unit volume).
  • the composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • Low-melting waxes are preferred for the preparation of a suppository, where mixtures of fatty acid glycerides and/or cocoa butter are suitable waxes.
  • the waxes may be melted, and the cyclohexylamine compound is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • the composition may include various materials which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule or cachet.
  • composition in solid or liquid form may include an agent which binds to the cyclohexylamine compound and thereby assists in the delivery of the active components.
  • Suitable agents which may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the present invention may consist of gaseous dosage units, e.g., it may be in the form of an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. Preferred aerosols may be determined by one skilled in the art, without undue experimentation.
  • the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in methods for either modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro, or used in the treatment of arrhythmia, diseases of the central nervous system, convulsion, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular diseases, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone m
  • the pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art.
  • the aminocyclohexyl compounds of the invention may be in the form of a solvate in a pharmaceutically acceptable solvent such as water or physiological saline.
  • the compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art.
  • the appropriate salt would be chosen to enhance bioavailability or stability of the compound for the appropriate mode of employment (e.g., oral or parenteral routes of administration).
  • a composition intended to be administered by injection can be prepared by combining the cyclohexylamine compound with water, and preferably buffering agents, so as to form a solution.
  • the water is preferably sterile pyrogen-free water.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the cyclohexylamine compound so as to facilitate dissolution or homogeneous suspension of the cyclohexylamine compound in the aqueous delivery system.
  • Surfactants are desirably present in aqueous compositions of the invention because the cyclohexylamine compounds of the present invention are typically hydrophobic.
  • Other carriers for injection include, without limitation, sterile peroxide-free ethyl oleate, dehydrated alcohols, propylene glycol, as well as mixtures thereof.
  • Suitable pharmaceutical adjuvants for the injecting solutions include stabilizing agents, solubilizing agents, buffers, and viscosity regulators.
  • these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators.
  • EDTA ethylenediaminetetraacetic acid
  • tartrate buffers citrate buffers
  • citrate buffers citrate buffers
  • high molecular weight polyethylene oxide viscosity regulators high molecular weight polyethylene oxide viscosity regulators.
  • ion channels such as cardiac sodium channels, are blocked in vitro or in vivo.
  • Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Their critical physiological roles include control of the electrical potential across the membrane, mediation of ionic and fluid balance, facilitation of neuromuscular and neuronal transmission, rapid transmembrane signal transduction, and regulation of secretion and contractility.
  • compounds that are capable of modulating the activity or function of the appropriate ion channels will be useful in treating or preventing a variety of diseases or disorders caused by defective or inadequate function of the ion channels.
  • the compounds of the invention are found to have significant activity in modulating ion channel activity both in vivo and in vitro.
  • the present invention provides for methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or preventing a disease or condition from arising in a warm-blooded animal, wherein a therapeutically effective amount of a compound of formula (I), or a composition containing a compound of formula (I) is administered to a warm-blooded animal in need thereof.
  • arrhythmia diseases of the central nervous system, convulsion, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular diseases, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other mental disorder, and alopecia.
  • the present invention provides a method for producing local analgesia or anesthesia in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I). These methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal.
  • the present invention provides a method wherein a preparation that contains ion channels is contacted with, or a warm-blooded animal (e.g., a mammal, such as a human) is administered an effective amount of an aminocyclohexyl ether compound of the invention.
  • a preparation that contains ion channels is contacted with, or a warm-blooded animal (e.g., a mammal, such as a human) is administered an effective amount of an aminocyclohexyl ether compound of the invention.
  • Suitable preparations containing cardiac sodium channels include cells isolated from cardiac tissue as well as cultured cell lines.
  • the step of contacting includes, for example, incubation of ion channels with a compound under conditions and for a time sufficient to permit modulation of the activity of the channels by the compound.
  • the compounds described above are provided for treating arrhythmia.
  • “treating arrhythmia” refers to both therapy for arrhythmia and for the prevention of arrhythmias occurring in a heart that is susceptible to arrhythmia.
  • An effective amount of a composition of the present invention is used to treat arrhythmia in a warm-blooded animal, such as a human.
  • Methods of administering effective amounts of antiarrhythmic agents are well known in the art and include the administration of an oral or parenteral dosage form.
  • Such dosage forms include, but are not limited to, parenteral dosage form.
  • Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants, and transdermal delivery systems.
  • oral or intravenous administration is preferred.
  • the dosage amount and frequency are selected to create an effective level of the agent without harmful effects. It will generally range from a dosage of from about 0.1 to about 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg where administered orally or intravenously for antiarrhythmic effect.
  • compositions of the present invention may be carried out in combination with the administration of other agents.
  • an opioid antagonist such as naloxone
  • a compound exhibits opioid activity where such activity may not be desired.
  • the naloxone may antagonize opioid activity of the administered compound without adverse interference with the antiarrhythmic activity.
  • an aminocyclohexyl ether compound of the invention may be co-administered with epinephrine in order to include local anesthesia.
  • a series of four tests may be conducted.
  • a compound of the present invention is given as increasing (doubling with each dose) intravenous boluses every 8 minutes to a pentobarbital anesthetized rat.
  • the effects of the compound on blood pressure, heart rate and the ECG are measured 30 seconds, 1, 2, 4 and 8 minutes after each dose.
  • Increasing doses are given until the animal dies.
  • the cause of death is identified as being of either respiratory or cardiac origin.
  • This test gives an indication as to whether the compound is modulating the activity of sodium channels and/or potassium channels, and in addition gives information about acute toxicity.
  • the indices of sodium channel blockade are increasing P-R interval and QRS widening of the ECG. Potassium channel blockade results in Q-T interval prolongation of the ECG.
  • a second test involves administration of a compound as an infusion to pentobarbital anesthetized rats in which the left ventricle is subjected to electrical square wave stimulation performed according to a preset protocol described in further detail below.
  • This protocol includes the determination of thresholds for induction of extrasystoles and ventricular fibrillation.
  • effects on electrical refractoriness are assessed by a single extra beat technique.
  • effects on blood pressure, heart rate and the ECG are recorded.
  • sodium channel blockers produce the ECG changes expected from the first test.
  • sodium channel blockers also raise the thresholds for induction of extrasystoles and ventricular fibrillation. Potassium channel blockade is revealed by increasing refractoriness and widening of the Q-T intervals of the ECG.
  • a third test involves exposing isolated rat hearts to increasing concentrations of a compound. Ventricular pressures, heart rate, conduction velocity and ECG are recorded in the isolated heart in the presence of varying concentrations of the compound. The test provides evidence for direct toxic effects on the myocardium. Additionally, selectivity, potency and efficacy of action of a compound can be ascertained under conditions simulating ischemia. Concentrations found to be effective in this test are expected to be efficacious in the electrophysiological studies.
  • a fourth test is estimation of the antiarrhythmic activity of a compound against the arrhythmias induced by coronary artery occlusion in anaesthetized rats. It is expected that a good antiarrhythmic compound will have antiarrhythmic activity at doses which have minimal effects on either the ECG, blood pressure or heart rate under normal conditions.
  • a compound on the ECG and responses to electrical stimulation are also assessed in intact, halothane anesthetized baboons ( Papio anubis ).
  • a blood pressure cannula and ECG electrodes are suitably placed in an anesthetized baboon.
  • a stimulating electrode is placed into the right ventricle, together with a monophasic action potential electrode.
  • ECG and electrical stimulation response to a compound reveal the possible presence of sodium and/or potassium channel blockade.
  • the monophasic action potential also reveals whether a compound widens the action potential, an action expected of a potassium channel blocker.
  • the pharmacological activity related to atrial arrhythmia e.g. atrial fibrillation and atrial flutter
  • atrial arrhythmia e.g. atrial fibrillation and atrial flutter
  • the following test may be performed.
  • the effects of a compound of the present invention on an animal's response to a sharp pain sensation the effects of a slight prick from a 7.5 g weighted syringe fitted with a 23 G needle as applied to the shaved back of a guinea pig ( Cavia porcellus ) is assessed following subcutaneous administration of sufficient (50 ⁇ l, 10 mg/ml) solution in saline to raise a visible bleb on the skin. Each test was done on the central area of the bleb and also on its periphery to check for diffusion of the test solution from the point of administration.
  • test animal produces a flinch in response to the stimulus, this demonstrates the absence of blockade of pain sensation.
  • Testing was carried out at intervals for up to 4 hours post administration. The sites of bleb formation were examined after 24 hours and showed no skin abnormalities consequent to local administration of test substances or of saline, the vehicle used for preparation of the test solutions.
  • kits that contain a pharmaceutical composition which includes one or more compounds of the above formulae.
  • the kit also includes instructions for the use of the pharmaceutical composition for modulating the activity of ion channels, for the treatment of arrhythmia or for the production of local analgesia and/or anesthesia, and for the other utilities disclosed herein.
  • a commercial package will contain one or more unit doses of the pharmaceutical composition.
  • such a unit dose may be an amount sufficient for the preparation of an intravenous injection.
  • compounds which are light and/or air sensitive may require special packaging and/or formulation.
  • packaging may be used which is opaque to light, and/or sealed from contact with ambient air, and/or formulated with suitable coatings or excipients.
  • the dichloromethane mixture was washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 8.5 g (100% yield) of the crude mesylate.
  • the basic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 7.16 g of the crude free aminoether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-chloroform (1:1, v/v) as eluent to yield 4.37 g of the pure free base.
  • the product was dissolved in ethyl ether (80 mL) and converted to the monohydrochloride salt by adding saturated solution of HCl in ethyl ether (80 mL).
  • the dichloromethane mixture was washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 9.0 g of the crude mesylate.
  • the acidic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL) and then basified to pH 10 with 50% sodium hydroxide aqueous solution.
  • the basic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 7.20 g of the crude free amino ether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent to provide the pure free base.
  • the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.7 g of the crude mesylate.
  • the acidic aqueous solution was extracted with ethyl ether (2 ⁇ 50 mL) and then basified to pH 10 with 50% sodium hydroxide aqueous solution.
  • the basic aqueous solution was extracted with ethyl ether (2 ⁇ 50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 3.67 g of the crude free amino ether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent to provide the pure free base.
  • the dichloromethane mixture was washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.3 g (100% yield) of the crude mesylate.
  • the remaining insoluble material was collected and recrystallized in boiling ethanol (75 mL) to provide a first crop of the desired product.
  • the acidic aqueous solution was basified to pH 10 with aqueous 50% NaOH and extracted with ether (2 ⁇ 50 mL).
  • the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide 1.6 g of the crude free amino ether.
  • the product was purified by chromatography on silica gel 60 (70–230 mesh) using a mixture of ethyl acetate-dichloromethane as eluent to yield 0.73 g of a pale yellow oil.
  • the dichloromethane mixture was washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.18 g of the crude mesylate.
  • the aqueous layer was basified to pH10 with 50% NaOH aqueous solution and extracted with ether (2 ⁇ 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) using a mixture of ethyl acetate and dichloromethane (1:1, v/v) as eluent to provide 2.8 g of a pale yellow oil.
  • the free base was dissolved in ether (80 mL) and converted to the monohydrochloride salt by adding a saturated solution of HCl in ether (80 mL).
  • the aqueous layer was basified to pH10 with 50% NaOH aqueous solution and extracted with ether (2 ⁇ 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) using a mixture of ethyl methanol and chloroform (2:8, v/v) as eluent.
  • the free amino ether was partially dissolved in ether (80 mL), insoluble materials were filtered off, and then a saturated solution of HCl in ether (80 mL) was added to the filtrate.
  • reaction mixture was washed with water (3 ⁇ 30 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 5.25 g of the crude mesylate.
  • the acidic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL) and then basified to pH10 with aqueous 50% sodium hydroxide.
  • the basic aqueous solution was extracted with ethyl ether (3 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 3.30 g of the crude free aminoether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate and dichloromethane (1:1, v/v) as eluent to provide the free base.
  • the product was dissolved in ethyl ether (100 mL) and converted to the monohydrochloride salt by adding a saturated solution of HCl in ethyl ether (100 mL). The solvent was evaporated in vacuo and the residue was dissolved in the minimum amount of boiling methanol to provide a first crop (0.7 g) of crystalline product on cooling. Addition of diethyl ether to the methanol filtrate provided a second crop (0.55 g). The two crops were combined to yield 1.25 g of the title compound, m.p. 158–160° C., having the elemental analysis indicated in Table 1.
  • reaction mixture was washed with water (2 ⁇ 30 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.24 g of the crude mesylate.
  • the reaction mixture was heated to 85° C. for 2 hours, then the temperature was reduced to 40° C. and the reaction stirred overnight.
  • the reaction mixture was poured into ice-water (800 mL) and extracted with ethyl acetate (3 ⁇ 200 mL).
  • the combined organic extracts were backwashed with a saturated aqueous solution (300 mL) of sodium chloride and dried over sodium sulfate.
  • Evaporation of the solvent in vacuo provided 8.2 g of an oil which was dissolved in ether (100 mL) and treated with a saturated solution of HCl in ether (100 mL). An oil precipitated and the solvent was evaporated in vacuo and the resulting crude hydrochloride salt was dissolved in water (200 mL).
  • the acidic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL) and then basified to pH 10 with an aqueous solution of sodium hydroxide (50% w/v).
  • the basic aqueous solution was extracted with ethyl ether (3 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 3.0 g of the crude free aminoether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent to provide the pure free base.
  • reaction mixture was washed with water (2 ⁇ 30 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 5.4 g of the crude mesylate.
  • the acidic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL) and then basified to pH 10 with an aqueous solution of sodium hydroxide (50% w/v).
  • the basic aqueous solution was extracted with ethyl ether (3 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 2.9 g of the crude free aminoether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent to provide the pure tree base.
  • reaction mixture was washed with water (2 ⁇ 30 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 5.9 g of the crude mesylate.
  • the acidic aqueous solution was extracted with ethyl ether (3 ⁇ 100 mL) and then basified to pH 10 with 50% aqueous sodium hydroxide solution.
  • the basic aqueous solution was extracted with ethyl ether (3 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 2.8 g of the crude free aminoether.
  • the crude product was purified by chromatography on silica gel 60 (70–230 mesh) with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent to provide the pure free base.
  • the dichloromethane mixture was washed with water (2 ⁇ 50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the crude mesylate.
  • the reaction mixture was heated to 90° C. for 90 min. and then the temperature was reduced to 45° C. and stirring continued overnight.
  • the reaction mixture was poured into ice-water (800 mL) and extracted with ethyl acetate (3 ⁇ 200 mL).
  • the combined organic extracts were backwashed with a saturated aqueous solution of sodium chloride (300 mL) and dried over sodium sulfate. Evaporation of the solvent in vacuo provided 8.5 g of the crude product which was dissolved in 15% HCl aqueous solution (200 mL) and extracted with ether (2 ⁇ 100 mL).
  • the aqueous layer was basified to pH10 with 50% NaOH aqueous solution and extracted with ether (2 ⁇ 100 mL).
  • reaction mixture was washed with water (2 ⁇ 30 mL) and the combined aqueous washings backextracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.87 g of the crude mesylate.
  • the basic aqueous solution was extracted with ethyl ether (2 ⁇ 100 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 3.58 g of the crude free aminoether.
  • the crude product was purified by chromatography column using silica gel 60, 70–230 mesh from BDH Inc. with a mixture of methanol and dichloromethane (2:8, v/v) as eluent to provide the pure free base.
  • the product was dissolved in diethyl ether (50 mL) and converted to the monohydrochloride salt by adding etheral HCl (50 mL). The solvent was evaporated in vacuo to yield 0.75 g of the title compound (not recrystallized).
  • reaction mixture was then washed with water (2 ⁇ 100 mL); the combined washings were back-extracted with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate suitable for the next step without any further purification.
  • the pH of the residual aqueous solution was adjusted to pH 5.7 with 6M HCl aqueous solution followed by extraction with diethyl ether (700 mL). The organic extract was concentrated in vacuo to yield the pure aminoether. The residual product was then partitioned between 1M HCl aqueous solution (300 mL) and dichloromethane (300 mL). The acidic aqueous solution was extracted twice more with dichloromethane (2 ⁇ 300 mL).
  • reaction mixture was then quenched with 1M HCl aqueous solution (350 mL) and the organic layer was collected.
  • the acidic aqueous layer was extracted with dichloromethane (2 ⁇ 150 mL) and the combined organic layers were dried over sodium sulfate. Evaporation in vacuo of the solvent provided 59.62 g of pale yellow oil, which was further pumped under high vacuum for 15 min to yield 58.23 g (17% over theoretical yield) of the crude title compound suitable for the next step without any further purification.
  • the reaction mixture was then diluted with more toluene (250 mL) and washed with saturated sodium bicarbonate aqueous solution (150 mL) and saturated sodium chloride aqueous solution (2 ⁇ 150 mL). The combined aqueous layers were back-extracted with toluene (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 79.6 g of dark oil.
  • the crude product was dissolved in ethanol (500 mL), and running it through a bed of activated carbon (80 g), decolorized the resulting solution. The charcoal was washed with more ethanol (1000 mL) and toluene (500 mL). The filtrate was concentrated in vacuo and further pumped under high vacuum for 1 hour to yield 63.25 g (6.8% over theoretical yield) of the crude title compound suitable for the next step without any further purification.
  • reaction mixture was then washed with a mixture of water-saturated sodium bicarbonate aqueous solution (1:1, v/v, 120 mL). The washing layer was collected and was back-extracted with dichloromethane (120 mL). The combined organic extracts were dried over sodium sulfate, the solvent was evaporated in vacuo and the residue was pumped under high vacuum for 4 hours to yield the crude mesylate suitable for the next step without any further purification.
  • the acidic aqueous layer was extracted with diethyl ether (2 ⁇ 500 mL) in order to extract unreacted 1-naphthenethanol.
  • the pH of the aqueous solution was adjusted to pH 4.8 with 5M NaOH aqueous solution and then extracted with diethyl ether (600 mL).
  • the aqueous solution was further basified to pH 5.7 and extracted with diethyl ether (600 mL). The same procedure was repeated at pH 6.5 and 12.1.
  • Analysis by gas chromatography of the different ether extracts showed that organic extracts at pH 4.8, 5.7 and 6.5 contained the title compound whereas ether extract at pH12.1 contained only unknown impurities.
  • the butanone was evaporated in vacuo and the residual aqueous solution was diluted to 250 mL with water.
  • the aqueous solution was extracted with diethyl ether (2 ⁇ 200 mL) and then with dichloromethane (2 ⁇ 200 mL).
  • the pooled dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo.
  • the residual oil was azeotropically dried with toluene.
  • the resulting sticky product was vigorously stirred overnight in diethyl ether (500 mL) with occasional scratching to trigger crystallization of the reaction product.
  • Compound #16 was prepared according to a procedure similar as the one depicted in FIG. 1 and further detailed in Example 14.
  • reaction mixture was then washed with water (2 ⁇ 50 mL) and the combined washings were back-extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate suitable for the next step without any further purification.
  • the residual oil was taken up with water (80 mL) and the resulting aqueous solution was acidified to pH 2 with 6M HCl aqueous solution.
  • the acidic aqueous solution was extracted with diethyl ether (3 ⁇ 40 mL) in order to extract the unreacted 2-naphthenethanol.
  • the pH of the aqueous layer was adjusted to pH10 with 50% NaOH aqueous solution and extracted with diethyl ether (3 ⁇ 40 mL).
  • the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude free aminoether.
  • Compound #17 was prepared in 10 steps according to the procedure described in Example 16. Steps (i) to (v) were identical to those in Example 16.
  • reaction mixture was washed with water (2 ⁇ 100 mL) and the combined washings were back-extracted with dichloromethane (120 mL).
  • dichloromethane 120 mL
  • the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate which was further pumped under high vacuum for 4 hours prior to use in step ix.
  • the residual aqueous solution was diluted with more water to a volume of 700 mL, acidified to pH 0.5 with 6M HCl aqueous solution and extracted with diethyl ether (2 ⁇ 600 mL). The pH of the aqueous layer was adjusted to pH 5.9 and then the aqueous solution was extracted with diethyl ether (700 mL). The organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 34.0 g of the title compound (70% yield).
  • the cooled reaction mixture was diluted with water (100 mL) and the organic solvent was evaporated in vacuo.
  • the organic layer was further diluted with water (400 mL), extracted with diethyl ether (500 mL) and with dichloromethane (2 ⁇ 600 mL).
  • the combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo.
  • Azeotropic distillation with toluene provided the title compound which was further dried under high vacuum for 15 min.
  • the hydrochloride salt was crystallized by triturating in diethyl ether, the crystals were collected and recrystallized from a mixture of ethanol-diethyl ether to yield 11.85 g of pure product (77% yield), having the elemental analysis indicated in Table 1.
  • the reaction mixture was quenched by addition of water ( ⁇ 70 mL), the organic solvent was evaporated in vacuo and the pH of the residual aqueous solution was adjusted to pH 9.6.
  • the aqueous layer was extracted with diethyl ether (2 ⁇ 70 mL), the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo.
  • the residue was then partitioned between 0.5M HCl aqueous solution (50 mL) and diethyl ether (2 ⁇ 50 mL).
  • the aqueous solution was basified to pH 5.9 and extracted with diethyl ether (50 mL).
  • the acidic aqueous solution was extracted with diethyl ether (2 ⁇ 50 mL), then basified to pH 5.0–5.5 with 5M NaOH aqueous solution and extracted with diethyl ether (3 ⁇ 50 mL).
  • the combined organic extracts at pH 5.05.5 were concentrated in vacuo to provide the crude title compound suitable for the next step without any further purification.
  • the cooled reaction mixture was concentrated in vacuo and the residual aqueous solution was diluted with water ( ⁇ 50 mL).
  • the acidic aqueous solution was extracted with diethyl ether (50 mL) and then with dichloromethane (3 ⁇ 50 mL).
  • the dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide the crude title compound.
  • the hydrochloride salt was crystallized by triturating in a mixture of diethyl ether-hexanes (1:1, v/v, ⁇ 200 mL) and then precipitated from a mixture of dichloromethane-diethyl ether-hexanes to yield 0.8 g of the title compound, having the elemental analysis indicated in Table 1.
  • the cooled reaction mixture was poured into water (40 mL) and the organic solvent was evaporated in vacuo.
  • the residual aqueous solution was diluted with more water (60 mL) and acidified to pH 0.5 with 6M HCl aqueous solution.
  • the acidic aqueous solution was extracted with diethyl ether (2 ⁇ 40 mL) and then the pH was adjusted to pH 5.5. Extraction with diethyl ether (3 ⁇ 50 mL) followed by drying over sodium sulfate and concentration in vacuo provided the pure aminoether.
  • the hydrochloride salt was precipitated by treatment of the free base with ethereal HCl. Recrystallization from a mixture of acetone-methanol-diethyl ether yielded 2.6 g (68% yield) of the title compound, having the elemental analysis indicated in Table 1.
  • Compound #24A was prepared from (1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane by reduction with sodium borohydride in a procedure similar to that described above for Compound #24.
  • the substrate (1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane was synthesized in analogy to the method described in Example 17.
  • Compound #25 was prepared in 10 steps according to a procedure identical to the one described in Examples 15 and 17. Steps (i) to (v) were identical to Example 15.
  • reaction mixture was diluted with dichloromethane (25 mL), washed with water (2 ⁇ 25 mL) and the combined washings were back-extracted with dichloromethane (25 mL).
  • the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate which was further pumped under high vacuum for 30 min. prior to use in step ix.
  • the acidic aqueous solution was extracted with diethyl ether (2 ⁇ 50 mL), the aqueous layer was collected and basified to pH 6.0. Extraction with diethyl ether (2 ⁇ 50 mL) followed by drying over sodium sulfate and evaporation of the solvent in vacuo yielded 1.55 g (43% yield) of the title compound.
  • the reaction mixture was concentrated in vacuo and the residue was partitioned between water (350 mL) and diethyl ether (350 mL). The aqueous layer was separated and extracted once more with diethyl ether (350 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide the crude product.
  • the crude aminoalcohol was purified by dry-column chromatography with a mixture of ethyl acetate-hexanes (1:1, v/v) as eluent to yield 4.83 g (47% yield) of the title compound.
  • the acidic aqueous solution was extracted with diethyl ether (3 ⁇ 100 mL), the combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo to provide the crude free base.
  • the product was purified by dry-column chromatography with a mixture of ethyl acetate-hexanes (1:10, v/v) as eluent to yield 2.4 g of the crude free aminoether.
  • the pure product (1.0 g) was converted to the hydrochloride salt by treatment with ethereal HCl and the resulting salt was recrystallized from a mixture of acetone-diethyl ether to yield 0.69 g of the title compound, having the elemental analysis indicated in Table 1.
  • the reaction mixture was further diluted with anhydrous methanol (7 mL) and stirred at room temperature for 16 hours.
  • the reaction mixture was quenched by addition of 6M HCl aqueous solution (40 mL), the organic solvent was evaporated in vacuo, the residual aqueous solution was diluted to 100 mL with water and the pH was adjusted to pH 0.5 with 6M HCl aqueous solution.
  • the acid aqueous layer was extracted with diethyl ether (100 mL); the aqueous layer was separated and basified to pH 6.7 with 5M NaOH aqueous solution.
  • Antiarrhythmic efficacy was assessed by investigating the effect of a compound on the incidence of cardiac arrhythmias in conscious rats subject to coronary artery occlusion. Rats weighing 200–300 gms were subjected to preparative surgery and assigned to groups in a random block design. In each case, the animal was anesthetized with halothane during surgical preparation. The left femoral artery was cannulated for measurement of mean arterial blood pressure and withdrawal of blood samples. The left femoral vein was also cannulated for injection of drugs. The thoracic cavity was opened and a polyethylene occluder loosely placed around the left anterior descending coronary artery. The thoracic cavity was then closed.
  • ECG was recorded by insertion of electrodes placed along the anatomical axis of the heart. All cannulae and electrode leads were exteriorized in the mid scapular region. In a random and double-blind manner, about 0.5 to 2 hours post-surgery, an infusion of vehicle, or the compound to be tested was given. After 15 minutes infusion, the occluder was pulled so as to produce coronary artery occlusion. ECG, arrhythmias, blood pressure, heart rate and mortality were monitored for 30 minutes after occlusion. Arrhythmias were recorded as ventricular tachycardia (VT) and ventricular fibrillation (VF) and scored according to Curtis, M. J. and Walker, M. J. A., Cardiovasc. Res. 22:656 (1988) (see Table 2).
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • VPB ventricular premature beats
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • Rats were excluded from the study if they did not exhibit pre-occlusion serum potassium concentrations within the range of 2.9–3.9 mM. Occlusion is associated with increases in R-wave height and “S-T” segment elevation; and an occluded zone (measured after death by cardiogreen dye perfusion) in the range of 25%–50% of total left-ventricular weight.
  • Table 3 describes the result of tests of the compounds described therein as values of a given infusion rate in micromol/kg/min. (ED 50 AA) which will reduce the arrhythmia score in treated animals to 50% of that shown by animals treated only with the vehicle in which the test drug(s) is dissolved.
  • Rats weighing 200–250 gms were used in this example. Animals were anesthetized with 60 mg/kg pentobarbitone i.p. The carotid artery and jugular vein were cannulated for measurement of blood pressure and drug injection, respectively. ECG was recorded by insertion of electrodes placed along the anatomical axis of the heart. All compounds were given as bolus injections.
  • the increases in P-R interval and QRS interval indicate cardiac sodium channel blockage while the increase in Q-T interval indicates ancillary cardiac potassium channel blockage which is the property of a type 1a antiarrhythmic.
  • Rats were prepared according to the preceding procedure. Two silver stimulating electrodes were inserted through the chest wall and implanted in the left ventricle. Square wave stimulation was used to determine threshold current for capture ventricular fibrillation threshold current, and effective refractory period (Howard, P. G. and Walker, M. J. A., Proc. West. Pharmacol. Soc. 33:123–127 (1990)). Table 5 contains ED 25 values for these indices of cardiac sodium channel blockage, where the ED 25 is the infusion rate in micromol/kg/minute of compound required to elicit a 25% increase from control. The increases in refractoriness indicate ancillary blockage of potassium channels.
  • the threshold current for capture is represented by “It”.
  • the fibrillation threshold current is represented by “VFT”.
  • the effective refracting period is represented by “ERP”.
  • Mongrel dogs of either sex weighing 15–49 kg were anesthetized with morphine (2 mg/kg im initially, followed by 0.5 mg/kg IV every 2 h) and ⁇ -chloralose (120 mg/kg IV followed by an infusion of 29.25 mg/kg/h; St.-Georges et al., 1997). Dogs were ventilated mechanically with room air supplemented with oxygen via an endotracheal tube at 20 to 25 breaths/minute with a tidal volume obtained from a nomogram. Arterial blood gases were measured and kept in the physiological range (SAO 2 >90%, pH 7.30–7.45).
  • Catheters were inserted into the femoral artery for blood pressure recording and blood gas measurement, and into both femoral veins for drug administration and venous sampling. Catheters were kept patent with heparinized 0.9% saline solution. Body temperature was maintained at 37–40° C. with a heating blanket.
  • the heart was exposed via a medial thoracotomy and a pericardial cradle was created.
  • Three bipolar stainless steel, TeflonTM-coated electrodes were inserted into the right atria for recording and stimulation, and one was inserted into the left atrial appendage for recording.
  • a programmable stimulator Digital Cardiovascular Instruments, Berkeley, Calif.
  • Two stainless steel, TeflonTM-coated electrodes were inserted into the left ventricle, one for recording and the other for stimulation.
  • a ventricular demand pacemaker (GBM 5880, Medtronics, Minneapolis, Minn.) was used to stimulate the ventricles at 90 beats/minute when (particular during vagal-AF) the ventricular rate became excessively slow.
  • the vagi were isolated in the neck, doubly-ligated and divided, and electrodes inserted in each nerve (see below).
  • nadolol was administered as an initial dose of 0.5 mg/kg iv, followed by 0.25 mg/kg IV every two hours.
  • AF rapid atrial pacing
  • the vagal stimulation voltage was adjusted under control conditions, and then readjusted after each treatment to maintain the same bradycardic effect.
  • AF was defined as rapid (>500 minute under control conditions), irregular atrial rhythm with varying electrogram morphology.
  • Diastolic threshold current was determined at a basic cycle length of 300 ms by increasing the current 0.1 mA incrementally until stable capture was obtained. For subsequent protocols current was set to twice diastolic threshold.
  • Atrial and ventricular ERP was measured with the extrastimulus method, over a range of S1S2 intervals at a basic cycle length of 300 ms. A premature extrastimulus S2 was introduced every 15 basic stimuli. The S1S2 interval was increased in 5 ms increments until capture occurred, with the longest S1S2 interval consistently failing to produce a propagated response defining ERP.
  • Diastolic threshold and ERP were determined in duplicate and averaged to give a single value. These values were generally within 5 ms.
  • AF cycle length was measured during vagal-AF by counting the number of cycles (number of beats ⁇ 1) over a 2-second interval at each of the atrial recording sites. The three AFCLs measurements were averaged to obtain an overall mean AFCL for each experimental condition.
  • vagal nerve stimulation was determined under control conditions in most experiments.
  • the vagal nerves were stimulated as described above with various voltages to determine the voltage which caused asystole (defined as a sinus pause greater than 3 seconds).
  • the response to vagal nerve stimulation was confirmed under each experimental condition and the voltage adjusted to maintain the heart rate response to vagal nerve stimulation constant.
  • vagal nerve stimulation was adjusted to a voltage which allowed two 20-minute episodes of vagal-AF to be maintained under control conditions (see below).
  • vagal-AF/electrophysiological testing protocol was repeated.
  • a pre-drug blood sample was obtained and vagal-AF reinstituted. Five minutes later, one of the treatments was administered at doses shown in Table 5. The total dose was infused over 5 minutes and a blood sample obtained immediately thereafter. No maintenance infusion was given. If AF terminated within 15 minutes, the electrophysiological measurements obtained under control conditions were repeated and a blood sample was obtained. If AF was not terminated by the first dose (within 15 minutes), a blood sample was obtained and vagal stimulation was discontinued to allow a return to sinus rhythm. The electrophysiological measurements were repeated and a third and final blood sample for this dose was obtained. AF was reinitiated and the vagal-AF/drug infusion/electrophysiological testing protocol was repeated until AF was terminated by the drug.
  • Group data are expressed as the mean ⁇ SEM.
  • Statistical analysis was carried out for effective doses for AFCL, and ERP using a t-test with a Bonterroini correction for multiple comparisons. Drug effects on blood pressure, heart rate, diastolic threshold and ECG intervals were assessed at the median dose for termination of AF. Two tailed tests were used and a p ⁇ 0.05 was taken to indicate statistical significance.
  • a single drug was administered to each dog over the dose range specified until AF was terminated.
  • the number of dogs in which AF was terminated at each dose is shown (number of dogs-dose, in ⁇ mol/kg).
  • the mean ⁇ SEM as well as the median dose required to terminate AF is shown.
  • Each dog received only one drug.
  • a number of the compounds of the present invention have been evaluated by this method. The results showed that all of the compounds tested are effective in terminating AF in the canine vagal-AF model. The conversion rates are similar to those reported for a variety of other class I and III drugs in this model. The effectiveness of flecainide as a control in the present study was comparable to that previously reported. All of the drugs prolonged AFCL prior to termination of AF; effects which are globally consistent with the wave length of re-entry model for termination of AF. The tested compounds of the present invention did not reduce blood pressure or heart rate at the median dose for termination of vagal-AF. The heart rate response to vagal nerve stimulation was similar in all groups and was not influenced by any of the compounds tested. Vagal nerve stimulation at 60% of the voltage required to produce asystole (10 ⁇ 1 V) produced a 1.3 ⁇ 0.1 second pause.
  • This model has been used to characterize the mechanisms of AF and atrial flutter (AFL). Waldo and colleagues have found that AF depends on reentry and that the site of termination is usually an area of slowed conduction.
  • This canine model is prepared by dusting the exposed atria with talcum powder followed by “burst” pacing the atria over a period of days after recovery. AF is inducible two days after surgery, however, by the fourth day after surgical preparation; sustainable atrial flutter is the predominant inducible rhythm. The inducibility of AF at day 2 is somewhat variable, such that only 50% of dogs may have sustained AF (generally ⁇ 60 minutes) for a requisite of 30 minutes.
  • Atrial flutter is more readily “mapped” for purposes of determining drug mechanisms. Inducibility of AF subsides after the fourth day post-surgery, similar to the AF that often develops following cardiac surgery that the sterile pericarditis model mimics. There may be an inflammatory component involved in the etiology of post-surgery AF that would provide a degree of selectivity to an ischaemia or acid selective drug. Similarly, while coronary artery bypass graft (CABG) surgery is performed to alleviate ventricular ischaemia, such patients may also be at risk for mild atrial ischaemia due to coronary artery disease (CAD).
  • CABG coronary artery bypass graft
  • Atrial flutter or fibrillation was induced 2 to 4 days after creation of sterile pericarditis in adult mongrel dogs weighing 19 kg to 25 kg. In all instances, the atrial fibrillation or flutter lasted longer than 10 minutes. All studies were performed in accordance with guidelines specified by our Institutional Animal Care and Use Committee, the American Heart Association Policy on Research Animal Use, and the Public Health Service Policy on Use of Laboratory Animals.
  • the canine sterile pericarditis model was created as previously described.
  • a pair of stainless steel wire electrodes coated with FEP polymer except for the tip were sutured on the right atrial appendage, Bachman's bundle and the posteroinferior left atrium close to the proximal portion of the coronary sinus. The distance between each electrode of each pair was approximately 5 mm.
  • These wire electrodes were brought out through the chest wall and exteriorized posteriorly in the interscapular region for subsequent use.
  • the dogs were given antibiotics and analgesics and then were allowed to recover. Postoperative care included administration of antibiotics and analgesics.
  • each dog was anesthetized with pentobarbital (30 mg/kg IV) and mechanically ventilated with 100% oxygen by use of a Boyle model 50 anesthesia machine (Harris-Lake, Inc.). The body temperature of each dog was kept within the normal physiological range throughout the study with a heating pad. With the dog anesthetized, but before the chest was opened, radiofrequency ablation of the His bundle was performed to create complete atrioventricular (AV) block by standard electrode catheter techniques. This was done to minimize the superimposition of atrial and ventricular complexes during subsequent recordings of unipolar atrial electrograms after induction of atrial flutter.
  • AV atrioventricular
  • an effective ventricular rate was maintained by pacing of the ventricles at a rate of 60 to 80 beats per minute with a Medtronic 5375 Pulse Generator (Medtronic Inc.) to deliver stimuli via the electrodes sutured to the right ventricle during the initial surgery.
  • Medtronic 5375 Pulse Generator Medtronic Inc.
  • AF/AFL For the induction of AF/AFL, one of two previously described methods was used: (1) introduction of one or two premature atrial beats after a train of 8 paced atrial beats at a cycle length of 400 ms, 300 ms, 200 ms, or 150 ms, or (2) rapid atrial Pacing for Periods of 1 to 10 seconds at rates incrementally faster by 10 to 50 beats per minute than the spontaneous sinus rate until atrial flutter was induced or there was a loss of 1:1 atrial capture. Atrial pacing was performed from either the right atrial appendage electrodes or the posteroinferior left atrial electrodes. All pacing was performed using stimuli of twice threshold for each basic drive train with a modified Medtronic 5325 programmable, battery-powered stimulator with a pulse width of 1.8 ms.
  • Atrial fib/flutter cycle length was measured and the initial mapping and analysis were performed to determine the location of the atrial fib/flutter reentrant circuit.
  • Atrial flutter was defined as a rapid atrial rhythm (rate, >240 beats per minute) characterized by a constant beat-to-beat cycle length, polarity, morphology, and amplitude of the recorded bipolar electrograms.
  • the relevant cloned cardiac ion channels (e.g. Kv1.4, Kv1.5, Kv4.2, Kv2.1 etc.) were studied by transient transfection into HEK cells using the mammalian expression vector pCDNA3. Transfections for each channel type were carried out separately to allow individual study of the ion channel of interest. Cells expressing channel protein were detected by cotransfecting cells with the vector pHook-1 (Invitrogen, San Diego, Calif., USA). This plasmid encoded the production of an antibody to the hapten phOX, which when expressed is displayed on the cell surface.
  • pHook-1 Invitrogen, San Diego, Calif., USA
  • Equal concentrations of individual channel and pHook DNA were incubated with 10 ⁇ concentration of lipofectAce in Modified Eagle's Medium (MEM, Canadian Life Technologies) and incubated with parent HEK cells plated on 25 mm culture dishes. After 3–4 hours the solution was replaced with a standard culture medium plus 20% fetal bovine serum and 1% antimycotic. Transfected cells were maintained in at 37 C in an air/5% CO2 incubator in 25 mm Petri dishes plated on glass coverslips for 24–48 hours to allow channel expression to occur. 20 min prior to experiments, cells were treated with beads coated with phOX. After 15 min, excess beads were washed off with cell culture medium and cells which had beads stuck to them were used for electrophysiological tests.
  • MEM Modified Eagle's Medium
  • control pipette filling solution contained (in mM): KCl, 130; EGTA, 5; MgCl2, 1; HEPES, 10; Na2ATP, 4; GTP, 0.1; and was adjusted to pH 7.2 with KOH.
  • the control bath solution contained (in mM): NaCl, 135; KCl, 5; sodium acetate, 2.8; MgCl2, 1; HEPES, 10; CaCl2, 1; and was adjusted to pH 7.4 with NaOH.
  • a low pH bath solution contained the same constituents as control bath, but pH was adjusted to 6.4 using NaOH. All chemicals were from Sigma Chemical Co. (St-Louis, Mo.).
  • the test ion channel modulating compound was dissolved to 10 mM stock solutions in water and used at concentrations between 0.5 and 100 uM. All compounds were protected from the light during all experiments.
  • Coverslips containing cells were removed from the incubator before experiments and placed in a superfusion chamber (volume 250 ⁇ l) containing the control bath solution at 22 C to 23 C. All recordings were made via the variations of the patch-clamp technique, using an Axopatch 200 A amplifier (Axon Instruments, CA). Patch electrodes were pulled from thin-walled borosilicate glass (World Precision Instruments; FL) on a horizontal micropipette puller, fire-polished, and filled with appropriate solutions. Electrodes had resistances of 1.0–2.5 ⁇ ohm when filled with control filling solution. Analog capacity compensation was used in all whole cell measurements. In some experiments, leak subtraction was applied to data.
  • Membrane potentials have not been corrected for any junctional potentials that arose between the pipette and bath solution. Data were filtered at 5 to 10 kHz before digitization and stored on a microcomputer for later analysis using the pClamp6 software (Axon Instruments, Foster City, Calif.). Due to the high level of expression of channel cDNA's in HEK cells, there was no need for signal averaging. The average cell capacitance was quite small, and the absence of ionic current at negative membrane potentials allowed faithful leak subtraction of data.
  • ⁇ block is the current decay time constant caused by the drug
  • [D] is the concentration of drug
  • k +1 and k ⁇ 1 are the apparent rate constants of binding and unbinding for the drug, respectively.
  • q represents the fractional electrical distance, i.e., the fraction of the transmembrane electrical field sensed by a single charge at the receptor site.
  • Kd* represents the binding affinity at the reference voltage (0 mV).
  • Blood pressure and a modified lead II ECG were recorded using a MACLAB 4S recording system paired with a Macintosh PowerBook (2400 c/180). A sampling rate of 1 kHz was used for both signals and all data was archived to a jazz disc for subsequent analysis.
  • Either of the vagi was isolated by blunt dissection and a pair of electrodes inserted into the nerve trunk.
  • the proximal end of the nerve was crushed using a vascular clamp and the nerve was stimulated using square wave pulses at a frequency of 20 Hz with a 1 ms pulse width delivered from the MACLAB stimulator.
  • the voltage (range 2–10V) was adjusted to give the desired bradycardic response.
  • the target bradycardic response was a reduction in heart rate by half. In cases where a sufficient bradycardic response could not be obtained, 10 ⁇ g/kg neostigmine iv was administered. This dose of neostigmine was also given after administration of the test drug in cases where the test drug had vagolytic actions.
  • test compounds were transported to Bogor, Indonesia on dry ice.
  • the actual doses varied slightly depending on the animals weight.
  • the test compounds were dissolved in saline immediately before administration.
  • vagal nerve stimulation was assessed by administering 2 mg/kg clofilium iv without stimulating the vagal nerve. Animals included in this experiment had previously received the same test compound 2–5 days prior to the experiment.
  • 30 second episodes of vagal nerve stimulation were recorded.
  • a five minute rest period was allowed between episodes and before starting the experiment.
  • the test solution was administered as an iv bolus at a rate of 5 ml/minute for 1 minute using an infusion pump (total volume 5 ml).
  • ECG and blood pressure responses were monitored continuously for 60 minutes and the occurrence of arrhythmias was noted.
  • Blood samples (1 ml total volume) were taken from each treated animal at the following times after drug administration: 30 seconds, 5, 10, 20, 30 and 60 minutes as well as 3, 6, 24 and 48 hours. Blood samples taken up to 60 minutes after drug administration were arterial while those taken after this time were venous. Samples were centrifuged, the plasma decanted and frozen. Samples were kept frozen before analysis of plasma concentration of the drug and potassium.
  • Guinea pigs were shaved (backs only) and 6 aliquots (50 ⁇ l) of compound solution (10 mg/ml) were injected just beneath the skin to form 6 blebs which were outlined with a permanent marker. Pain responses were assessed as above on each bleb at regular intervals up to 4 hours post injection and the duration of pain blockage was recorded for three animals for each test solution.

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US7534790B2 (en) 2009-05-19
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